Neurology Central

Early-onset Alzheimer’s disease linked to high LDL cholesterol levels

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Researchers at the Atlanta Veterans Affair Medical Center (GA, USA) and Emory University (GA, USA) have discovered a link between high LDL cholesterol levels and early-onset Alzheimer’s disease.

The results, which have been published in JAMA Neurology, could potentially aid clinicians to understand how the disease develops and what the possible causes are, including genetic variation.

“The big question is whether there is a causal link between cholesterol levels in the blood and Alzheimer’s disease risk,” commented Thomas Wingo (Emory University), lead author of the study. “The existing data have been murky on this point. One interpretation of our current data is that LDL cholesterol does play a causal role.”

“If that is the case, we might need to revise targets for LDC cholesterol to help reduce Alzheimer’s risk. Our work is now focused on testing whether there is a causal link.”

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To examine whether early-onset Alzheimer’s disease is linked to cholesterol and identify the genetic variants that may be responsible, the researchers sequenced specific genomic regions of 2125 individuals: 654 of whom had early-onset Alzheimer’s and 1471 of who were controls. The investigators also tested blood samples of 267 participants in order to measure the amount of LDL cholesterol present.

They found that APOE-E4 explained approximately 10% of early-onset Alzheimer’s, which is similar to estimates in late-onset Alzheimer’s disease. The researchers also tested for APP, PSEN1 and PSEN2, and revealed that about 3% of early-onset Alzheimer’s cases had at least one of these known risk factors.

After testing the blood samples, the team found that participants with elevated LDL levels were most likely to have early-onset Alzheimer’s disease, compared with people whom had lower cholesterol levels. According to the investigators, this was true even after they controlled for cases with the APOE mutation.

The researchers did not find a link between HDL cholesterol levels and early-onset Alzheimer’s, and only a very slight association between the disease and triglyceride levels.

Moreover, the researchers also found a new possible genetic risk factor for early-onset Alzheimer’s, as the disease cases were higher in participants with a rare gene variant called APOB. This gene encodes a protein that is involved in the metabolism of lipids, including cholesterol.

This finding suggests a direct link between the rare APOB mutation and Alzheimer’s disease risk, according to the researchers. However, the link between LDL-C level and early-onset Alzheimer’s was not fully explained by APOE or APOB, suggesting that other genes and mechanisms also increase disease risk.

Sources: Wingo TS, Cutler DJ, Wingo AP et al. Association of early-onset Alzheimer’s disease with elevated low-density lipoprotein cholesterol levels and rare genetic coding variants of APOB. JAMA Neurol. doi:10.1001/jamaneurol.2019.0648 (2019) (Epub ahead of print); www.eurekalert.org/pub_releases/2019-05/varc-hll052419.php

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